Reproduction and embryonic development are complex processes involving multiple genetically determined events. The elucidation of the proteins involved in normal and abnormal reproductive and early embryonic development is a critical step in the understanding of these processes. The activins and the inhibins, members of a large family of growth regulatory proteins that includes the transforming growth factors beta's, bone morphogenetic proteins, and Mullerian inhibiting substance, have been implicated to play physiologic roles in multiple tissues as endocrine, paracrine, and autocrine mediators during embryonic and adult reproduction and development. In particular, activins have been implicated to play important roles in mesoderm induction, neuronal survival, and pituitary and gonadal function. To understand the roles of the activins in mammalian reproduction and development, I have taken a multifaceted approach to generate transgenic mice deficient in the activin subunits, activin type II receptors, and the activin binding protein, folIistatin. Germline transmission of mutant activin betaA, activin receptor II, and foIlistatin genes has already been achieved initial investigations of follistatin-deficient mice, which die at birth, indicate an essential role for follistatin in modulating activin action during embryonic development. The goal of this proposal is to extensively characterize the phenotype of mice generated in these "loss of function" experiments. Unlike in vitro assays, these studies will reveal the essential and physiologic roles of the activins, activin receptors, and follistatin, and in particular will address the functions of these proteins in embryonic development (e.g., mesoderm induction) and in adult reproductive physiology (e.g., pituitary-gonadal homeostasis). The aims of these studies are: 1) Characterize why follistatin-deficient mice die at birth; 2) Generate and analyze mice deficient in the activin betaA subunit; 3) Generate and analyze mice deficient in the activin type II receptor; and 4) Generate and analyze mice deficient in multiple activin subunits (betaA and betaB subunits) or activin receptors (type II and IIB) by interbreeding to evaluate functional redundancy. These studies will facilitate the understanding of the roles of the activin ligands, receptors, and binding protein in mammalian development and reproduction and will identify some of the critical genetic loci involved in these processes.